Lung cancer remains the leading cause of cancer-related death. A major reason is the lack of an effective screening strategy to diagnose lung cancer at an early stage. One approach to designing an early detection and chemoprevention strategy is to identify and characterize the lung epithelial cell of origin for this cancer. Tissue specific stem cells are essential for the maintenance and regeneration of an injured organ. By virtue of their properties, they are also implicated as the cell of origin of tumors. Thus the cancer stem cells retain the unlimited proliferative potential of normal stem cells, but are no longer subject to physiologic control. They are also implicated in cancer recurrence as they are able to escape the chemotherapy mediated cell death by becoming quiescent. Recent studies have identified a Bronchioalveolar stem cell (BASC) niche in the lung. BASCs are present in small numbers at the bronchioalveolar ductal junction. BASCs are thought to be the tissue stem cells that lead to the repopulation of the terminal bronchiolar and the alveolar epithelia after injury. They have also been postulated to be the target cell of adenocarcinomas based on studies in Ras-induced lung cancer models. Using a novel transgenic strategy, I propose to genetically mark these cells and to conditionally ablate them in the adult mouse. These tools will allow me to identify the BASCs in lung sections, to trace their lineage and to study the developmental pathways, such as Hedgehog, activated following lung injury. Most importantly, the ability to conditionally ablate BASCs will directly test the importance of these cells in lung regeneration after injury and in the formation and maintenance of adenocarcinomas. This research work is performed under the mentorship of Dr. Matthew Scott, a pioneer in Hedgehog signaling in cancer, and in close collaboration with Dr. Allan Balmain, a renowned skin and lung cancer geneticist and an expert in stem cell fate decisions. I plan to devote 80% of my time in this research with full support and commitment from the Departments of Developmental Biology and Oncology at Stanford University and 20% of my time in clinical and didactic activities. This career development plan would lead me to realize my long term goal of a full time independent tenure track investigator in cancer biology. RELEVANCE (See instructions): Stem cells in adults are normally used for injury repair and tissue maintenence. But these cells may loose regulation and become cancerous. This study seeks to define the lung stem cells and their role in lung cancer. This study will have a potential impact in the early detection of lung cancer and an improved understanding of cancer recurrence leading to new therapies.